Statin-carboxyalkylether combinations

ABSTRACT

The invention is a pharmaceutical composition comprising a carboxyalkylether which lowers triglycerides and elevated HDL, and a statin which inhibits HMG-CoA reductase, thereby reducing LDL, said composition being useful for treating vascular diseases.

FIELD OF THE INVENTION

This invention concerns a combination of a statin compound, which isknown to cause a reduction in plasma levels of low-density lipoprotein(LDL) cholesterol, and a carboxyalkylether, a compound which causes arise in high-density lipoprotein (HDL) cholesterol. The combination isuseful for treating vascular disorders and diabetes mellitus.

BACKGROUND OF THE INVENTION

Several clinical studies have established that lowering certain forms ofcholesterol in a mammal is an effective way to treat and prevent heartattacks, sudden death, and angina, both in subjects having higher thannormal levels of circulating cholesterol, as well as those having normallevels of cholesterol. Lowering LDL, the bad form of cholesterol, is nowone of the primary objectives of physicians treating patients who have,or who have a high risk of developing, cardiovascular diseases such ascoronary heart disease, atherosclerosis, myocardial infarction, stroke,cerebral infarction, and even restenosis following balloon angioplasty.Many physicians are now utilizing cholesterol lowering agents purely asa prophylactic treatment in healthy subjects whose cholesterol levelsare normal, thereby guarding against development of cardiovasculardiseases.

The most commonly used cholesterol lowering agents are the statins,which are compounds which inhibit the enzyme3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzymeresponsible for catalyzing the conversion of HMG-CoA to mevalonate,which is an early and rate-limiting step in the cholesterol biosyntheticpathway.

There are several forms of circulating blood cholesterol which occurnaturally in mammals. Some forms are considered “bad” cholesterol, whileother forms are considered “good” cholesterol and are essential for goodhealth. The good form of cholesterol has been established to be HDL. Abad cholesterol is LDL. Another form of LDL cholesterol, the primary badform, is a modified form of LDL called lipoprotein(a), or “Lp(a)”. Highlevels of Lp(a) are now believed to be detrimental and can lead tocardiovascular diseases, and is one of the major risk factors leading todeath from heart disease.

Because vascular diseases such as coronary heart disease, stroke, andeven peripheral vascular disease, remain a leading cause of death anddisability throughout the world, the need continues to develop new andimproved treatments, as well as agents that will actually prevent theformation of these diseases.

We have now discovered that treatment and prevention of vasculardiseases can be effected by administering a combination of a statin witha carboxyalkylether. Typical carboxyalkylethers are described in U.S.Pat. No. 5,648,387 incorporated herein by reference.

SUMMARY OF THE INVENTION

This invention provides a pharmaceutical composition comprised of aneffective amount of a statin and an effective amount of acarboxyalkylether. More particularly, the invention is a combination ofa statin with a carboxyalkylether having Formula I

wherein

-   n and m independently are integers from 2 to 9;-   R₁, R₂, R₃, and R₄ independently are C₁-C₆ alkyl, C₁-C₆ alkenyl,    C₂-C₆ alkynyl, and R₁ and R₂ together with the carbon to which they    are attached, and R₃ and R₃ together with the carbon to which they    are attached, can complete a carbocyclic ring having from 3 to 6    carbons;-   Y₁ and Y₂ independently are COOH, CHO, tetrazole, and COOR₅ where R₅    is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; and-   where the alkyl, alkenyl, and alkynyl groups may be substituted with    one or two groups selected from halo, hydroxy, C₁-C₆ alkoxy, and    phenyl.

Preferred compounds to be employed in this invention have the aboveformula wherein n and m are the same integer, and wherein R₁, R₂, R₃,and R₄ each are alkyl.

Further preferred are compounds wherein Y₁ and Y₂ independently are COOHor COOR₅ where R₅ is alkyl.

The most preferred compounds to be employed have the Formula II

wherein n and m are each an integer selected from 2, 3, 4, or 5, ideally4 or 5.

An especially preferred compound has the Formula III

The combinations of this invention can also employ the pharmaceuticallyacceptable salts of the acids of Formula I.

Typical statins to be employed in combination with the compound ofFormula I include atorvastatin, simvastatin, pravastatin, cerivastatin,mevastatin, velostatin, fluvastatin, lovastatin, dalvastatin, andfluindostatin. The statins can be employed as pharmaceuticallyacceptable salts.

A particularly preferred composition of this invention utilizes acarboxyalkylether of Formula II together with a statin selected fromatorvastatin calcium, pravastatin sodium, simvastatin, lovastatin, andcerivastatin. The most preferred composition employs the compound ofFormula III with atorvastatin calcium.

Also provided by the invention are methods for treating vasculardiseases such as peripheral vascular disease, coronary heart disease,stroke, and restenosis. The invention provides a method for loweringLp(a), plasma triglycerides, very low-density lipoprotein (VLDL)cholesterol, LDL cholesterol, and apolipoprotein B. The inventionadditionally provides a method for elevating plasma HDL cholesterol,apolipoprotein A-I, and apolipoprotein E. The invention also provides amethod for treating and preventing noninsulin-dependent diabetesmellitus by increasing insulin sensitivity by administering acombination of this invention.

DETAILED DESCRIPTION OF THE INVENTION

We have discovered that combining a statin with a carboxyalkyletherprovides a surprisingly effective composition for treating andpreventing vascular diseases, as well as diabetes mellitus. As notedabove, the “carboxyalkylethers” as used herein are compounds such asthose described in U.S. Pat. No. 5,648,387 incorporated herein byreference. The compounds can be the free acid, a salt form, or thetetrazolyl or aldehyde analog.

The other active component of the combinations of this invention is astatin. The term “statin”, where used in the specification and theappendant claims, is synonymous with the terms“3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor” and “HMG-CoAreductase inhibitor.” These three terms are used interchangeablythroughout the specification and appendant claims. As the synonymssuggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme Areductase and, as such, are effective in lowering the level of bloodplasma cholesterol. Statins and pharmaceutically acceptable saltsthereof are particularly useful in lowering low-density lipoproteincholesterol (LDL-C) levels in mammals and particularly in humans.

The HMG-CoA reductase inhibitors suitable for use herein include, butare not limited to, simvastatin, pravastatin, rivastatin, mevastatin,fluindostatin, cerivastatin, velostatin, fluvastatin, dalvastatin,dihydrocompactin, compactin, or lovastatin; or a pharmaceuticallyacceptable salt of simvastatin, pravastatin, rivastatin, cerivastatin,mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin,dihydrocompactin, compactin, lovastatin, or pharmaceutically acceptablesalts thereof. However, it is to be noted that atorvastatin calcium is aparticularly preferred statin to be employed in the present combination.See U.S. Pat. No. 5,273,995 incorporated herein by reference.

The statins disclosed herein are prepared by methods well-known to thoseskilled in the art. Specifically, simvastatin may be prepared accordingto the method disclosed in U.S. Pat. No. 4,444,784, which isincorporated herein by reference. Pravastatin may be prepared accordingto the method disclosed in U.S. Pat. No. 4,346,227, which isincorporated herein by reference. Cerivastatin may be prepared accordingto the method disclosed in U.S. Pat. No. 5,502,199, which isincorporated herein by reference. Cerivastatin may alternatively beprepared according to the method disclosed in European PatentApplication Publication No. EP617019. Mevastatin may be preparedaccording to the method disclosed in U.S. Pat. No. 3,983,140, which isincorporated herein by reference. Velostatin may be prepared accordingto the methods disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No.4,450,171, both of which are incorporated herein by reference.Fluvastatin may be prepared according to the method disclosed in U.S.Pat. No. 4,739,073, which is incorporated herein by reference. Compactinmay be prepared according to the method disclosed in U.S. Pat. No.4,804,770, which is incorporated herein by reference. Lovastatin may beprepared according to the method disclosed in U.S. Pat. No. 4,231,938,which is incorporated herein by reference. Dalvastatin maybe preparedaccording to the method disclosed in European Patent ApplicationPublication No. 738510 A2. Fluindostatin may be prepared according tothe method disclosed in European Patent Application Publication No.363934 A1. Dihydrocompactin may be prepared according to the methoddisclosed in U.S. Pat. No. 4,450,171, which is incorporated herein byreference.

It will be recognized that certain of the above statins contain either afree carboxylic acid or a free amine group as part of the chemicalstructure. Further, certain statins within the scope of this inventioncontain lactone moieties, which exist in equilibrium with the freecarboxylic acid form. These lactones can be maintained as carboxylatesby preparing pharmaceutically acceptable salts of the lactone. Thus,this invention includes pharmaceutically acceptable salts of thosecarboxylic acids or amine groups. The expression “pharmaceuticallyacceptable salts” includes both pharmaceutically acceptable acidaddition salts and pharmaceutically acceptable cationic salts. Theexpression “pharmaceutically acceptable cationic salts” is intended todefine but is not limited to such salts as the alkali metal salts,(e.g., sodium and potassium), alkaline earth metal salts (e.g., calciumand magnesium), aluminum salts, ammonium salts, and salts with organicamines such as benzathine (N,N′-dibenzylethylenediamine), choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine),benethamine (N-benzylphenethylamine), diethylamine, piperazine,tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. Theexpression “pharmaceutically acceptable add addition salts” is intendedto define but is not limited to such salts as the hydrochloride,hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate(mesylate) and p-toluenesulfonate (tosylate) salts.

The pharmaceutically acceptable cationic salts of statins containingfree carboxylic acids may be readily prepared by reacting the free acidform of the statin with an appropriate base, usually one equivalent, ina co-solvent. Typical bases are sodium hydroxide, sodium methoxide,sodium ethoxide, sodium hydride, potassium methoxide, magnesiumhydroxide, calcium hydroxide, benzathine, choline, diethanolamine,piperazine, and tromethamine. The salt is isolated by concentration todryness or by addition of a non-solvent. In many cases, salts arepreferably prepared by mixing a solution of the acid with a solution ofa different salt of the cation (sodium or potassium ethylhexanoate,magnesium oleate), employing a solvent (e.g., ethyl acetate) from whichthe desired cationic salt precipitates, or can be otherwise isolated byconcentration and/or addition of a non-solvent.

The pharmaceutically acceptable acid addition salts of statinscontaining free amine groups may be readily prepared by reacting thefree base form of the statin with the appropriate acid. When the salt isof a monobasic acid (e.g., the hydrochloride, the hydrobromide, thep-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid(e.g., the hydrogen sulfate, the succinate), or the dihydrogen form of atribasic acid (e.g., the dihydrogen phosphate, the citrate), at leastone molar equivalent and usually a molar excess of the acid is employed.However, when such salts as the sulfate, the hemisuccinate, the hydrogenphosphate, or the phosphate are desired, the appropriate and exactchemical equivalents of acid will generally be used. The free base andthe acid are usually combined in a co-solvent from which the desiredsalt precipitates, or can be otherwise isolated by concentration and/oraddition of a non-solvent.

In addition, the carboxyalkylethers and pharmaceutically acceptable acidaddition salts thereof may occur as hydrates or solvates. Further, thestatins of the instant invention and the pharmaceutically acceptablesalts of the statins of the instant invention may also occur as hydratesor solvates. Said hydrates and solvates are also within the scope of theinvention.

The pharmaceutical combinations and methods of this invention are alladapted to therapeutic use as agents in the prevention and treatment ofatherosclerosis, angina pectoris, and a condition characterized by thepresence of both hypertension and hyperlipidemia in mammals,particularly humans. Further, since these diseases and conditions areclosely related to the development of cardiac disease and adversecardiac conditions, these combinations and methods, by virtue of theiraction as antiatherosclerotics, antianginals, antihypertensives, andantihyperlipidemics are useful in the management of cardiac risk insubjects at risk of developing adverse cardiac conditions and insubjects at risk of suffering adverse cardiac events.

The utility of the compositions of the present invention as medicalagents in the treatment of atherosclerosis in mammals (e.g., humans) isdemonstrated by the activity of the compounds of this invention inconventional assays and in a clinical protocol such as those describedbelow.

EXAMPLE 1

The metabolic effects of atorvastatin calcium (CI-981) and the compoundof Formula III (CI-1027), alone and in combination, were evaluated inrats according to the following protocol.

Male Sprague-Dawley rats weighing from 201 to 225 grams were purchasedfrom Charles Rivers Laboratories. The animals were fed a highcholesterol chow diet (Ralston Purina Chow 150), and given water adlibitum. Atorvastatin calcium (CI-981 at 30 mg/kg) and6,6′-oxybis-(2,2-dimethylhexanoic acid calcium salt (CI-1027 at 30mg/kg) were suspended individually, and the combination of 30 mg/kg ofCI-981 plus 10 mg/kg of CI-11027 was suspended, in a mixture of 1.5%carboxymethylcellulose (sodium salt, low viscosity, Sigma item C-8758,St. Louis, Mo.) plus 0.2% Tween-20 (Sigma item P-1379, St. Louis, Mo.).The suspensions were administered by oral gavage to each test animal(each dose regimen was given to 8 [N=8] test animals) between 6:00 and9:00 AM each day for 14 days. A group of control animals (N=8) receivedthe vehicle alone. After 14 days of treatment blood samples were drawn,and plasma levels of lipid and lipoprotein were determined. The resultsare presented below in Table 1. TABLE 1 Effects of Two Weeks ofTreatment With CI-981, CI-1027, and Combination CI-981 + CI-1027 in ChowFed Rats Treatment Triglycerides Total Cholesterol VLDL LDL HDL HDLGroup mg/kg/day N (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) VLDL + LDLControl 8 118 ± 11  41 ± 1 6.1 ± 0.6 11.3 ± 0.8 23 ± 1 1.37 ± 0.10CI-981 30 8 87 ± 11 49 ± 3 7.9 ± 1.0 19.1 ± 1.6 22 ± 2 0.86 ± 0.11CI-1027 10 8 58 ± 9  58 ± 4 3.2 ± 0.6  3.4 ± 0.4 52 ± 4 8.57 ± 0.99CI-981 + CI-1027 30/10 8 63 ± 8  49 ± 2 5.6 ± 1.0 11.1 ± 1.7 33 ± 2 2.59± 0.62

Table 2 below shows the percentage (%) change in the treatment groupscompared to the control group. TABLE 2 Percentage Change From ControlsCaused by CI-981, CI-1027, and Combination CI-981 + CI-1027 in Chow FedRats Triglycerides HDL Control mg/kg/day N (% change) Total CholesterolVLDL LDL HDL VLDL + LDL 8 0 0 0 0 0 0 CI-981 30 8 −26 +19 +30 +69 −4 −37CI-1027 10 8 −51 +42 −48 −70 +126 +526 CI-981 + CI-1027 30/10 8 −47 +19−8 −2 +43 +89

EXAMPLE 2

The above experiment was repeated using genetically altered mice, namelyLDL receptor knockout mice. LDLr(−\−) mice were obtained from JacksonLaboratories. A colony was established and maintained. Female mice wereselected for the experiment, and were maintained on a normal chow diet(Ralston Purina), and water was available ad libitum. The mice werehoused 2 to 4 per cage in temperature controlled (24° C.) rooms on a12-hour light/12-hour dark cycle (lights were turned on at 6:00 AMdaily), prior to and during the experiment. The test compounds wereformulated as suspensions in the same vehicle as described in Example 1(1.5% carboxymethyl-cellulose plus 0.2% Tween-20). Both CI-981 andCI-1027 were formulated for individual doses of 30 and 60 mg/kg. Thecombination of CI-981+CI-1027 was formulated for doses of 30 mg/kgCI-981+30 mg/kg CI-1027, and 60 mg/kg CI-981+60 mg/kg CI-1027. A groupof 10 animals (N=10) were used as controls, and received vehicle alone.One group of 10 mice received CI-981 alone; a second group of 10 micereceived CI-1027 alone; a third group of 10 mice received thecombination of CI-981+CI-1027 (30 mg/kg+30 mg/kg); and the fourth groupof 10 mice received the combination of CI-981+CI-1027 (60 mg/kg+60mg/kg). The animals received doses of test compounds by oral gavagebetween 6:00 and 9:00 AM daily for 14 days. The animals were sacrificedat the end of Day 14, and blood samples were taken and analyzed forlipid and lipoprotein content. The results are presented in Table 3below. TABLE 3 Effects of Two Weeks of Treatment With CI-981, CI-1027,and Combination CI-981 + CI-1027 in LDL Receptor Knockout MiceTriglycerides Total Cholesterol VLDL LDL HDL HDL Control mg/kg/day N(mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) VLDL + LDL 10 79 ± 7 329 ± 236.3 ± 0.5 246 ± 20  76 ± 6  0.32 ± 0.03 CI-981 60 10 86 ± 5 261 ± 2311.8 ± 2.4  192 ± 24  57 ± 5  0.33 ± 0.04 CI-1027 60 10 110 ± 20 208 ±13 11.2 ± 4.0  110 ± 12  85 ± 11 0.84 ± 0.15 CI-981 + CI-1027 30/30 1088 ± 9 173 ± 10 8.1 ± 2.0 104 ± 9  62 ± 5   0.6 ± 0.08 CI-981 + CI-102760/60 10 90 ± 7 139 ± 12 8.5 ± 2.7 70 ± 8  60 ± 3  0.83 ± 0.07

Table 4 below shows the percentage (%) change in the treatment groupcompared to the control group. TABLE 4 Percentage Change From ControlsCaused by CI-981, CI-1027, and CI-981 + CI-1027 in LDL Receptor KnockoutMice Triglycerides Total Cholesterol VLDL LDL HDL HDL Control mg/kg/dayN (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) VLDL + LDL 10 0 0 0 0 0 0CI-981 60 10 9 −21 87 −22 −25 3 CI-1027 60 10 39 −37 78 −55 12 162CI-981 + CI-1027 30/30 10 11 −47 29 −58 −19 88 CI-981 + CI-1027 60/60 1014 −58 35 −72 −21 159

The foregoing data from Examples 1 and 2 establish a dramatic andsurprising metabolic effect achieved by combining a statin with acarboxyalkylether according to this invention.

EXAMPLE 3 Effect of Compound of Formula III and a Statin, Alone and inCombination, on the Treatment of Atherosclerosis

This study is a prospective randomized evaluation of the effect of acombination of the compound of Formula III (compound III) or apharmaceutically acceptable salt thereof and a statin on theprogression/regression of coronary and carotid artery disease. The studyis used to show that a combination of the compound of Formula III or apharmaceutically acceptable acid addition salt and a statin such asatorvastatin calcium is effective in slowing or arresting theprogression or causing regression of existing coronary artery disease(CAD) as evidenced by changes in coronary angiography or carotidultrasound, in subjects with established disease.

This study is an angiographic documentation of coronary artery diseasecarried out as a double-blind, placebo-controlled trial of a minimum ofabout 500 subjects and preferably of about 780 to about 1200 subjects.It is especially preferred to study about 1200 subjects in this study.Subjects are admitted into the study after satisfying certain entrycriteria set forth below.

Entry criteria: Subjects accepted for entry into this trial must satisfycertain criteria. Thus, the subject must be an adult, either male orfemale, aged 18 to 80 years of age in whom coronary angiography isclinically indicated. Subjects will have angiographic presence of asignificant focal lesion such as 30% to 50% on subsequent evaluation byquantitative coronary angiography (QCA) in a minimum of one segment(non-PTCA, non-bypassed, or non-MI vessel) that is judged not likely torequire intervention over the next 3 years. It is required that thesegments undergoing analysis have not been interfered with. Sincepercutaneous transluminal cardiac angioplasty (PTCA) interferes withsegments by the insertion of a balloon catheter, non-PTCA segments arerequired for analysis. It is also required that the segments to beanalyzed have not suffered a thrombotic event, such as a myocardialinfarct (MI). Thus, the requirement for non-MI vessels. Segments thatwill be analyzed include: left main, proximal, mid and distal leftanterior descending, first and second diagonal branch, proximal anddistal left circumflex, first or largest space obtuse marginal,proximal, mid and distal right coronary artery. Subjects will have anejection fraction of greater than 30% determined by catheterization orradionuclide ventriculography or ECHO cardiogram at the time of thequalifying angiogram or within the previous 3 months of the acceptanceof the qualifying angiogram provided no intervening event such as athrombotic event or procedure such as PTCA has occurred.

Generally, due to the number of patients and the physical limitations ofany one facility, the study is carried out at multiple sites. At entryinto the study, subjects undergo quantitative coronary angiography aswell as B-mode carotid artery ultrasonography and assessment of carotidarterial compliance at designated testing centers. This establishesbaselines for each subject. Once admitted into the test, subjects arerandomized to receive the compound of Formula III (200 mg) and placeboor a statin (dose is dependent upon the particular statin used; however,generally 80 mg will be used at first) and placebo or compound III (200mg) and a statin (80 mg). It will be recognized by a skilled person thatthe free base form or other salt forms of compound III or the free baseform or other salt forms of the statin may be used in this invention.Calculation of the dosage amount for these other forms of the statin andcompound III is easily accomplished by performing a simple ratiorelative to the molecular weights of the species involved. The amount ofcompound III may be varied as required. Generally, a subject will startout taking 200 mg, and the amount will be titrated down to as little as50 mg as determined by the clinical physician. The amount of the statinwill similarly be titrated down from 80 mg if it is determined by thephysician to be in the best interests of the subject. The subjects aremonitored for a 1- to 3-year period, generally 3 years being preferred.B-mode carotid ultrasound assessment of carotid artery atherosclerosisand compliance are performed at regular intervals throughout the study.

Generally, 6-month intervals are suitable. Typically this assessment isperformed using B-mode ultrasound equipment. However, a person skilledin the art may use other methods of performing this assessment. Coronaryangiography is performed at the conclusion of the I— to 3-year treatmentperiod. The baseline and posttreatment angiograms and the interveningcarotid artery B-mode ultrasonograms are evaluated for new lesions orprogression of existing atherosclerotic lesions. Arterial compliancemeasurements are assessed for changes from baseline and over the 6-monthevaluation periods.

The primary objective of this study is to show that the combination ofcarboxyalkylether or a pharmaceutically acceptable acid addition saltand a statin reduces the progression of atherosclerotic lesions asmeasured by quantitative coronary angiography (QCA) in subjects withclinical coronary artery disease. QCA measures the opening in the lumenof the arteries measured.

The primary endpoint of the study is the change in the average meansegment diameter of the coronary artery tree. Thus, the diameter of anarterial segment is measured at various portions along the length ofthat segment. The average diameter of that segment is then determined.After the average segment diameter of many segments has been determined,the average of all segment averages is determined to arrive at theaverage mean segment diameter. The mean segment diameter of subjectstaking a statin and compound III or a pharmaceutically acceptable acidaddition salt will decline more slowly, will be halted completely, orthere will be an increase in the mean segment diameter. These resultsrepresent slowed progression of atherosclerosis, no change in theprogression of atherosclerosis, and regression of atherosclerosis,respectively.

The secondary objective of this study is that the combination ofcarboxyalkylether or a pharmaceutically acceptable acid addition saltand a statin reduces the rate of progression of atherosclerosis in thecarotid arteries as measured by the slope of the maximum intimal-medialthickness measurements averaged over 12 separate wall segments (MeanMax) as a function of time, more than does compound III or apharmaceutically acceptable acid addition salt or a statin alone. Theintimal-medial thickness of subjects taking a statin and compound III ora pharmaceutically acceptable salt thereof will increase more slowly,will cease to increase, or will decrease. These results represent slowedprogression of atherosclerosis, halted progression of atherosclerosis,and regression of atherosclerosis, respectively. Further, these resultsmay be used to facilitate dosage determinations.

The utility of the compounds of the present invention as medical agentsin the treatment of angina pectoris in mammals (e.g., humans) isdemonstrated by the activity of the compounds of this invention inconventional assays and the clinical protocol described below.

EXAMPLE 4 Effect of Compound of Formula III and a Statin, Alone and inCombination, on the Treatment of Angina

This study is a double-blind, parallel-arm, randomized study to show theeffectiveness of compound III or a pharmaceutically acceptable acidaddition salt thereof and a statin given in combination in the treatmentof symptomatic angina.

Entry criteria: Subjects are males or females between 18 and 80 years ofage with a history of typical chest pain associated with one of thefollowing objective evidences of cardiac ischemia: (1) stress testsegment elevation of about one millimeter or more from the ECG; (2)positive treadmill stress test; (3) new wall motion abnormality onultrasound; or (4) coronary angiogram with a significant qualifyingstenosis. Generally a stenosis of about 30% to 50% is considered to besignificant.

Each subject is evaluated for about 10 to 32 weeks. At least 10 weeksare generally required to complete the study. Sufficient subjects areused in this screen to ensure that about 200 to 800 subjects andpreferably about 400 subjects are evaluated to complete the study.Subjects are screened for compliance with the entry criteria, set forthbelow, during a 4-week run-in phase. After the screening criteria aremet, subjects are washed out from their current anti-anginal medicationand stabilized on a long acting nitrate such as nitroglycerine,isosorbide-5-mononitrate or isosorbide dinitrate. The term “washed out”,when used in connection with this screen, means the withdrawal ofcurrent anti-anginal medication so that substantially all of saidmedication is eliminated from the body of the subject. A period of 8weeks is preferably allowed for both the washout period and for theestablishment of the subject on stable doses of said nitrate. Subjectshaving one or two attacks of angina per week while on stable doses oflong acting nitrate are generally permitted to skip the washout phase.After subjects are stabilized on nitrates, the subjects enter therandomization phase provided the subjects continue to have either one ortwo angina attacks per week. In the randomization phase, the subjectsare randomly placed into one of the four arms of the study set forthbelow. After completing the washout phase, subjects in compliance withthe entry criteria undergo 24-hour ambulatory electrocardiogram (ECG)such as Holter monitoring, exercise stress testing such as a treadmill,and evaluation of myocardial perfusion using photon emission tomography(PET) scanning to establish a baseline for each subject. When conductinga stress test, the speed of the treadmill and the gradient of thetreadmill can be controlled by a technician. The speed of the treadmilland the angle of the gradient are generally increased during the test.The time intervals between each speed and gradient increase is generallydetermined using a modified Bruce Protocol.

After the baseline investigations have been completed, subjects areinitiated on one of the following four arms of the study: (1) placebo;(2) a statin (about 2.5 mg to about 160 mg); (3) compound III (about 25mg to about 200 mg); or (4) a combination of the above doses of compoundIII and a statin together. The subjects are then monitored for 2 to 24weeks. It will be recognized by a skilled person that the free base formor other salt forms of compound III or the free base form or other saltforms of the statin may be used in this invention. Calculation of thedosage amount for these other forms of the statin and compound III iseasily accomplished by performing a simple ratio relative to themolecular weights of the species involved.

After the monitoring period has ended, subjects will undergo thefollowing investigations: (1) 24-hour ambulatory ECG, such as Holtermonitoring; (2) exercise stress testing (e.g., treadmill using saidmodified Bruce Protocol); and (3) evaluation of myocardial perfusionusing PET scanning. Patients keep a diary of painful ischemic events andnitroglycerine consumption. It is generally desirable to have anaccurate record of the number of anginal attacks suffered by the patientduring the duration of the test. Since a patient generally takesnitroglycerin to ease the pain of an anginal attack, the number of timesthat the patient administers nitroglycerine provides a reasonablyaccurate record of the number of anginal attacks.

To demonstrate the effectiveness and dosage of the drug combination ofthis invention, the person conducting the test will evaluate the subjectusing the tests described. Successful treatment will yield fewerinstances of ischemic events as detected by ECG, will allow the subjectto exercise longer or at a higher intensity level on the treadmill or toexercise without pain on the treadmill, or will yield better perfusionor fewer perfusion defects on PET.

The utility of the compounds of the present invention as medical agentsin the treatment of hypertension and hyperlipidemia in mammals (e.g.,humans) suffering from a combination of hypertension and hyperlipidemiais demonstrated by the activity of the compounds of this invention inconventional assays and the clinical protocol described below.

EXAMPLE 5 Effects of Carboxyalkylether and a Statin, Alone and inCombination, on the Treatment of Subjects Having Both Hypertension andHyperlipidemia

This study is a double-blind, parallel-arm, randomized study to show theeffectiveness of carboxyalkylether or a pharmaceutically acceptable acidaddition salt thereof and a statin given in combination in controllingboth hypertension and hyperlipidemia in subjects who have mild,moderate, or severe hypertension and hyperlipidemia.

Each subject is evaluated for 10 to 20 weeks and preferably for 14weeks. Sufficient subjects are used in this screen to ensure that about400 to 800 subjects are evaluated to complete the study.

Entry criteria: Subjects are male or female adults between 18 and 80years of age having both hyperlipidemia and hypertension. The presenceof hyperlipidemia is evidenced by evaluation of the LDL cholesterollevel of the subject relative to certain positive risk factors. If thesubject has no coronary heart disease (CHD) and has less than twopositive risk factors, then the subject is considered to havehyperlipidemia, which requires drug therapy if the LDL of the subject is≧190 mg/dL. If the subject has no CHD and has two or more positive riskfactors, then the subject is considered to have hyperlipidemia, whichrequires drug therapy if the LDL of the subject is ≧160 mg/dL. If thesubject has CHD, then the subject is considered to have hyperlipidemiaif the LDL of the subject is ≧130 mg/dL.

Positive risk factors include: (1) male over 45, (2) female over 55wherein said female is not undergoing hormone replacement therapy (HRT),(3) family history of premature cardiovascular disease, (4) the subjectis a current smoker, (5) the subject has diabetes, (6) an HDL of lessthan 45 mg/dL, and (7) the subject has hypertension. An HDL of >60 mg/dLis considered a negative risk factor and will offset one of the abovementioned positive risk factors.

The presence of hypertension is evidenced by a sitting diastolic bloodpressure (BP) of >90 mmHg or sitting systolic BP of >140 mmHg. All bloodpressures are generally determined as the average of three measurementstaken 5 minutes apart.

Subjects are screened for compliance with the entry criteria set forthabove. After all screening criteria are met, subjects are washed outfrom their current antihypertensive and lipid lowering medication andare placed on the NCEP ATP II Step 1 diet. The NCEP ATP II (adulttreatment panel, 2nd revision) Step 1 diet sets forth the amount ofsaturated and unsaturated fat which can be consumed as a proportion ofthe total caloric intake. The term “washed out”, where used inconnection with this screen, means the withdrawal of currentantihypertensive and lipid lowering medication so that substantially allof said medication is eliminated from the body of the subject. Newlydiagnosed subjects generally remain untreated until the test begins.These subjects are also placed on the NCEP Step 1 diet. After the 4-weekwashout and diet stabilization period, subjects undergo the followingbaseline investigations: (1) blood pressure and (2) fasting lipidscreen. The fasting lipid screen determines baseline lipid levels in thefasting state of a subject. Generally, the subject abstains from foodfor 12 hours, at which time lipid levels are measured.

After the baseline investigations are performed, subjects are started onone of the following: (1) a fixed dose of compound III, generally about25 to 200 mg; (2) a fixed dose of a statin, generally about 2.5 mg toabout 160 mg; or (3) a combination of the above doses of compound IIIand a statin together. It will be recognized by a skilled person thatthe free base form or other salt forms of compound III or the free baseform or other salt forms of the statin may be used in this invention.Calculation of the dosage amount for these other forms of the statin andcompound III is easily accomplished by performing a simple ratiorelative to the molecular weights of the species involved. Subjectsremain on these doses for a minimum of 6 weeks, and generally for nomore than 8 weeks. The subjects return to the testing center at theconclusion of the 6 to 8 weeks so that the baseline evaluations can berepeated. The blood pressure of the subject at the conclusion of thestudy is compared with the blood pressure of the subject upon entry. Thelipid screen measures the total cholesterol, LDL-cholesterol,HDL-cholesterol, triglycerides, apoB, very low-density lipoprotein(VLDL) and other components of the lipid profile of the subject.Improvements in the values obtained after treatment relative topretreatment values indicate the utility of the drug combination.

The utility of the compounds of the present invention as medical agentsin the management of cardiac risk in mammals (e.g., humans) at risk foran adverse cardiac event is demonstrated by the activity of thecompounds of this invention in conventional assays and the clinicalprotocol described below.

EXAMPLE 6 Effects of Carboxyalkylether and a Statin, Alone and inCombination, on Subjects at Risk of Future Cardiovascular Events

This study is a double-blind, parallel-arm, randomized study todemonstrate the effectiveness of carboxyalkylether or a pharmaceuticallyacceptable acid addition salt and a statin given in combination inreducing the overall calculated risk of future events in subjects whoare at risk for having future cardiovascular events. This risk iscalculated by using the Framingham Risk Equation. A subject isconsidered to be at risk of having a future cardiovascular event if thatsubject is more than one standard deviation above the mean as calculatedby the Framingham Risk Equation. The study is used to evaluate theefficacy of a fixed combination of carboxylalkylether or apharmaceutically acceptable acid addition salt and a statin incontrolling cardiovascular risk by controlling both hypertension andhyperlipidemia in patients who have both mild to moderate hypertensionand hyperlipidemia.

Each subject is evaluated for 10 to 20 weeks and preferably for 14weeks. Sufficient subjects are recruited to ensure that about 400 to 800subjects are evaluated to complete the study.

Entry criteria: Subjects included in the study are male or female adultsubjects between 18 and 80 years of age with a baseline 5-year risk,which risk is above the median for said subject's age and sex, asdefined by the Framingham Heart Study, which is an ongoing prospectivestudy of adult men and women showing that certain risk factors can beused to predict the development of coronary heart disease. The age, sex,systolic and diastolic blood pressure, smoking habit, presence orabsence of carbohydrate intolerance, presence or absence of leftventricular hypertrophy, serum cholesterol, and HDL of more than onestandard deviation above the norm for the Framingham Population are allevaluated in determining whether a patient is at risk for adversecardiac event. The values for the risk factors are inserted into theFramingham Risk Equation and calculated to determine whether a subjectis at risk for a future cardiovascular event.

Subjects are screened for compliance with the entry criteria set forthabove. After all screening criteria are met, patients are washed outfrom their current antihypertensive and lipid lowering medication andany other medication which will impact the results of the screen. Thepatients are then placed on the NCEP ATP II Step 1 diet, as describedabove. Newly diagnosed subjects generally remain untreated until thetest begins. These subjects are also placed on the NCEP ATP II Step 1diet. After the 4-week washout and diet stabilization period, subjectsundergo the following baseline investigations: (1) blood pressure; (2)fasting; (3) lipid screen; (4) glucose tolerance test; (5) ECG; and (6)cardiac ultrasound. These tests are carried out using standardprocedures well-known to persons skilled in the art. The ECG and thecardiac ultrasound are generally used to measure the presence or absenceof left ventricular hypertrophy.

After the baseline investigations are performed, patients will bestarted on one of the following: (1) a fixed dose of compound III (about25 to 200 mg); (2) a fixed dose of a statin (about 2.5 mg to about 160mg); or (3) the combination of the above doses of compound III and astatin. Patients are kept on these doses and are asked to return in 6 to8 weeks so that the baseline evaluations can be repeated. At this time,the new values are entered into the Framingham Risk Equation todetermine whether the subject has a lower, greater, or no change in therisk of future cardiovascular event.

The above assays demonstrating the effectiveness of compound III orpharmaceutically acceptable acid addition salts thereof and atorvastatinor pharmaceutically acceptable salts thereof in the treatment of anginapectoris, atherosclerosis, hypertension and hyperlipidemia together, andthe management of cardiac risk, also provide a means whereby theactivities of the compounds of this invention can be compared betweenthemselves and with the activities of other known compounds. The resultsof these comparisons are useful for determining dosage levels inmammals, including humans, for the treatment of such diseases.

The following dosage amounts and other dosage amounts set forthelsewhere in this specification and in the appendant claims are for anaverage human subject having a weight of about 65 kg to about 70 g. Theskilled practitioner will readily be able to determine the dosage amountrequired for a subject whose weight falls outside the 65 to 70 kg range,based upon the medical history of the subject and the presence ofdiseases, e.g., diabetes, in the subject. All doses set forth herein,and in the appendant claims, are daily doses.

In general, in accordance with this invention, the carboxyalkylether isgenerally administered in a dosage of about 25 mg to about 500 mg.Preferably, compound III is administered in a dosage of about 5 mg toabout 100 mg. It will be recognized by a skilled person that the freebase form or other salt forms of compound III may be used in thisinvention. Calculation of the dosage amount for these other forms of orthe free base form or other salt forms of compound III is easilyaccomplished by performing a simple ratio relative to the molecularweights of the species involved.

In general, in accordance with this invention, the above statins areadministered in the following dosage amounts:

-   -   Simvastatin, generally about 2.5 mg to about 160 mg and        preferably about 10 mg to about 40 mg;    -   Pravastatin, generally about 2.5 mg to about 160 mg and        preferably about 10 mg to about 40 mg;    -   Cerivastatin, generally about 25 μg to about 5 mg and preferably        about 1 mg to about 3.2 mg;    -   Fluvastatin, generally about 2.5 mg to about 160 mg and        preferably about 20 mg to about 80 mg;    -   Lovastatin, generally about 2.5 mg to about 160 mg and        preferably about 10 mg to about 80 mg; and    -   Atorvastatin, generally about 2.5 mg to about 160 mg and        preferably about 10 mg to about 80 mg.

It will be recognized by a skilled person that the free base form orother salt forms of the above statins may be used in this invention.Calculation of the dosage amount for these other forms of or the freebase form or other salt forms said statins is easily accomplished byperforming a simple ratio relative to the molecular weights of thespecies involved.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablecarrier or diluent. Thus, the compounds of this invention can beadministered either individually or together in any conventional oral,parenteral, or transdermal dosage form.

For oral administration, a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate, and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate,and talc are often very useful for tableting purposes. Solidcompositions of a similar type are also employed as fillers in soft- andhard-filled gelatin capsules; preferred materials in this connectionalso include lactose or milk sugar, as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the compounds of this invention can becombined with various sweetening agents, flavoring agents, coloringagents, emulsifying agents, and/or suspending agents, as well as suchdiluents as water, ethanol, propylene glycol, glycerin, and various likecombinations thereof.

The combinations of this invention may also be administered in acontrolled release formulation such as a slow release or a fast releaseformulation. Such controlled release formulations of the combination ofthis invention may be prepared using methods well-known to those skilledin the art. The method of administration will be determined by theattendant physician or other person skilled in the art after anevaluation of the subject's condition and requirements. The generallypreferred formulation of atorvastatin calcium is Lipitor® as describedin U.S. Pat. No. 5,686,104 incorporated herein by reference.

For purposes of parenteral administration solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous, and intraperitoneal injection purposes. In thisconnection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples, seeRemington's Pharmaceutical Sciences, Mack Publishing Company, Easter,Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain 0.1%to 95% of the compound(s) of this invention, preferably 1% to 70%. Inany event, the composition or formulation to be administered willcontain a quantity of a compound(s) according to the invention in anamount effective to treat the condition or disease of the subject beingtreated.

Since the present invention relates to the treatment of diseases andconditions with a combination of active ingredients which may beadministered separately, the invention also relates to combiningseparate pharmaceutical compositions in kit form. The kit includes twoseparate pharmaceutical compositions: a carboxyalkylether or apharmaceutically acceptable acid addition salt thereof and a statin or apharmaceutically acceptable salt thereof. The kit includes containermeans for containing the separate compositions such as a divided bottleor a divided foil packet; however, the separate compositions may also becontained within a single, undivided container. Typically, the kitincludes directions for the administration of the separate components toachieve synergistic results. The kit form is particularly advantageouswhen the separate components are preferably administered in differentdosage forms (e.g., oral and parenteral), are administered at differentdosage intervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

1. A pharmaceutical composition comprising: a. an amount of acarboxyalkylether or a pharmaceutically acceptable acid addition saltthereof; b. an amount of a statin or a pharmaceutically acceptable saltthereof; and c. a pharmaceutically acceptable carrier or diluent.
 2. Apharmaceutical composition of claim 1 wherein said statin isatorvastatin, simvastatin, pravastatin, rivastatin, mevastatin,fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin,compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptablesalt thereof.
 3. A pharmaceutical composition of claim 2 wherein saidstatin is atorvastatin, simvastatin, pravastatin, mevastatin,lovastatin, cerivastatin, or pharmaceutically acceptable salts thereof.4. A pharmaceutical composition comprising: a. an amount of acarboxyalkylether of Formula I or a pharmaceutically acceptable acidaddition salt thereof;

wherein n and m independently are integers from 2 to 9: R₁, R₂, R₃ andR₄ independently are C₁-C₆ alkyl C₁-C₆ alkenyl, C₂-C₆ alkynyl, and R₁and R₂ together with the carbon to which they are attached, and R₃ andR₄ together with the carbon to which they are attached, can complete acarbocyclic ring having from 3 to 6 carbons; Y₁ and Y₂ independently areCOOH, CHO, tetrazole, and COOR₅ where R₅ is C₁-C₆ alkyl C₂-C₆ alkenyl,C₂-C₆ alkynyl; and wherein the alkyl alkenyl, and alkynyl groups may besubstituted with one or two groups selected from halo, hydroxy, C I—C₆alkoxy, and phenyl; b. an amount of a statin or a pharmaceuticallyacceptable salt thereof; and c. a pharmaceutically acceptable carrier ordiluent.
 5. A pharmaceutical composition of claim 4 comprisingatorvastatin calcium and 6,6′-oxybis(2,2-dimethylhexanoic acid) or apharmaceutically acceptable acid addition salt thereof.
 6. A firstpharmaceutical composition for use with a second pharmaceuticalcomposition for achieving a hypolipidemic effect in a mammal sufferingfrom hyperlipidemia, which effects are greater than the sum of thehypolipidemic effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of a carboxyalkylether or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent, said firstpharmaceutical composition comprising an amount of a statin or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent.
 7. A composition of claim 6 wherein saidstatin is atorvastatin, simvastatin, pravastatin, rivastatin,mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin,dihydrocompactin, compactin, cerivastatin, or lovastatin; or apharmaceutically acceptable salt of simvastatin, pravastatin,rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin,dalvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin.8. A composition of claim 7 wherein said second pharmaceuticalcomposition comprises 6,6′-oxybis(2,2-dimethylhexanoic acid) or apharmaceutically acceptable acid addition salt thereof.
 9. A firstpharmaceutical composition for use with a second pharmaceuticalcomposition for achieving a hypolipidemic effect in a mammal sufferingfrom hyperlipidemia, which effects are greater than the sum of thehypolipidemic effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of a statin or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount of acompound of Formula II

or a pharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent.
 10. A composition ofclaim 9 wherein said statin is atorvastatin, simvastatin, pravastatin,rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin,dalvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin;or a pharmaceutically acceptable salt thereof.
 11. A composition ofclaim 10 comprising 6,6′-oxybis(2,2-dimethylhexanoic acid) or apharmaceutically acceptable acid addition salt thereof.
 12. A firstpharmaceutical composition for use with a second pharmaceuticalcomposition for managing cardiac risk in a mammal at risk of sufferingan adverse cardiac event, which effect is greater than the sum of thecardiac risk management effects achieved by administering said first andsecond pharmaceutical compositions separately, and which secondpharmaceutical composition comprises an amount of a statin or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent, said first pharmaceutical compositioncomprising an amount of a carboxyalkylether or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically acceptablecarrier or diluent.
 13. A composition of claim 12 wherein said statin isatorvastatin, simvastatin, pravastatin, rivastatin, mevastatin,fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin,compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptablesalt of simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin,velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, orlovastatin.
 14. A composition of claim 13 comprising6,6′-oxybis(2,2-dimethylhexanoic acid) or a pharmaceutically acceptableacid addition salt thereof.
 15. A kit for achieving a therapeutic effectin a mammal comprising: a. an amount of a carboxyalkylether or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent in a first unit dosageform; b. an amount of a statin or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier or diluent in a secondunit dosage form; and c. container means for containing said first andsecond dosage forms.
 16. A kit of claim 15 wherein said statin isatorvastatin, simvastatin, pravastatin, rivastatin, mevastatin,fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin,compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptablesalt of simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin,velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin,cerivastatin, or lovastatin.
 17. A kit of claim 16 comprising acarboxyalkylether of Formula I or a pharmaceutically acceptable acidaddition salt thereof.
 18. A kit of claim 17 employing6,6′-oxybis(2,2-dimethylhexanoic acid) or a pharmaceutically acceptableacid addition salt thereof.
 19. A kit of claim 15 wherein saidtherapeutic effect is treatment of hyperlipidemia.
 20. A kit of claim 15wherein said therapeutic effect is treatment of angina pectoris.
 21. Akit of claim 15 wherein said therapeutic effect is treatment of cardiacrisk.
 22. A kit of claim 15 wherein said therapeutic effect is treatmentof atherosclerosis.
 23. A kit of claim 22 wherein said treatment ofatherosclerosis slows the progression of atherosclerotic plaques.
 24. Akit of claim 23 wherein said progression of atherosclerotic plaques isslowed in coronary arteries.
 25. A kit of claim 23 wherein saidprogression of atherosclerotic plaques is slowed in carotid arteries.26. A kit of claim 23 wherein said progression of atheroscleroticplaques is slowed in the peripheral arterial system.
 27. A kit of claim22 wherein said treatment of atherosclerosis causes the regression ofatherosclerotic plaques.
 28. A kit of claim 27 wherein said regressionof atherosclerotic plaques occurs in coronary arteries.
 29. Apharmaceutical composition of claim 5 comprising atorvastatin calciumand 6,6′-oxybis(2,2-dimethylhexanoic acid) calcium salt. 306,6′-Oxybis(2,2-dimethylhexanoic acid) monocalcium salt.